This project is exploring the role of oxidative metabolism in the antitumor activity of phagocytes and lymphocytes in mouse and man. H2O2 appears to be involved in the antitumor activity of activated mouse peritoneal macrophages in 3 circumstances: when pharmacologic agents are added which stimulate the respiratory burst; when antitumor antibody is present; or when the tumor cells are coated with eosinophil peroxidase. Tumor cells defend themselves against oxidative injury in large part through the cyclic oxidation and reduction of glutathione. The GSH redox cycle can be slowed down by inactivating GSSG reductase with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), by reducing GSH peroxidase through dietary selenium deprivation, and by reducing tumor cell GSH levels through interruption of GSH synthesis or augmented consumption. Tumor cells can be killed in vivo in the peritoneal cavity by H2O2 generated by a solid-phase enzyme; this effect can be enhanced by BCNU. The production of H2O2 by macrophages is suppressed by tumor cells. Human monocyte H2O2 and O2.-secretion fall markedly during maturation into macrophages in vitro. These changes are not explained on the basis of the concomitant changes in cellular superoxide dismutase, myeloperoxidase, catalase, GSH, GSSG reductase, or GSH peroxidase, but can be reversed by lymphokines. The areas outlined above will be explored further, along with the possibility of the involvement of oxidative metabolism in T cell-mediated cytotoxicity.